A critical analysis of codon optimization in human therapeutics
Open accessAbstract
Codon optimization describes gene engineering approaches that use synonymous codon changes to increase protein production. Applications for codon optimization include recombinant protein drugs and nucleic acid therapies, including gene therapy, mRNA therapy, and DNA/RNA vaccines. However, recent reports indicate that codon optimization can affect protein conformation and function, increase immunogenicity, and reduce efficacy. We critically review this subject, identifying additional potential hazards including some unique to nucleic acid therapies. This analysis highlights the evolved complexity of codon usage and challenges the scientific bases for codon optimization. Consequently, codon optimization may not provide the optimal strategy for increasing protein production and may decrease the safety and efficacy of biotech therapeutics. We suggest that the use of this approach is reconsidered, particularly for in vivo applications.
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Codon optimization, the conventional approach to mRNA design, optimizes codon usage but barely improves stability.
“Conversely, codon optimization11,12, the conventional approach to mRNA design, optimizes codon usage but barely improves stability, leaving out the huge space of highly stable mRNAs.”
From Algorithm for optimized mRNA design improves stability and immunogenicity (2023) · cites this paper as [11]
The sections on the history of codon optimization and on optimizing codon usage describe its broad use and its focus on changing codon assignments to increase protein expression. The Assumption 2 section says synonymous changes can affect mRNA stability, but it does not say codon optimization barely improves stability or that it leaves out a large space of highly stable mRNAs. No page number is available in our copy. (LLM, conf=0.84)
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“Because of the redundancy of the genetic code, uridine content of mRNA can also be reduced by selecting codons that lack uridine in the “wobble” position.(35) Such “uridine-depleted”mRNAs generated higher genome-editing activity after each of three repeated doses than their original sequence counterparts (Figure 2E).”
BackgroundRecent innovations in mRNA vaccines
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- Authors
- Mauro, V. P., & Chappell, S. A.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Mauro, Vincent P.
- ORCID
- Mauro, Vincent P.
- Venue
- Trends in Molecular Medicine
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 20
- Issue
- 11
- Pages
- 604-613
- ISSN
- 1471-4914 (ISSN-L)
- PMC
- PMC4253638
- OpenAlex
- W2024266527
- Cited by
- 343
- References
- 125
- Citations by year
- 2026: 30 · 2025: 44 · 2024: 45 · 2023: 38 · 2022: 51 · 2021: 39 · 2020: 25 · 2019: 24 · 2018: 21 · 2017: 11 · 2016: 11 · 2015: 3 · 2014: 1
- FWCI
- 0.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Trends in Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM078071, GM078071)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Keywords
- codon optimization, synonymous codons, recombinant protein expression, nucleic acid therapeutics, mRNA therapeutics, DNA vaccine, gene therapy, immunogenicity, protein conformation, codon usage, in vivo gene delivery
- MeSH terms
- Animals, Codon, Gene Expression Regulation, Genetic Engineering, Humans, Peptides, Recombinant Proteins, RNA, Messenger, RNA, Transfer, Protein Engineering, Genetic Therapy, RNA Editing
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